Periodontal disease refers to bacterially mediated inflammation of the gingiva (gingivitis) accompanied by a loss of periodontal attachment to one or more teeth (periodontitis). Gingivitis is detected by a red, swollen gingival margin that bleeds on gentle probing. Periodontitis is detected by exposure of the tooth's enamel-cemental junction and underlying cementum in the oral cavity, directly (recession) or within a deep gingival sulcus (pocket). Gingivitis and chronic periodontitis, by far the most common forms, are caused by bacteria that adhere to teeth and develop into a plaque (biofilm) that may become calcified at the gingival margin. In the late stages of periodontitis, so much support is lost that the teeth become loose and may exfoliate, creating a major problem for older humans and animals. The difficulty in chewing interferes with eating an adequate diet and the persistent bacterial colonization induces deleterious systemic effects throughout the body.
The gingiva is composed of free and attached portions. The free gingiva is the soft tissue side of the gingival sulcus, normally 1-2 mm in length. The sulcular side of the free gingiva is covered with oral sulcular epithelium and the oral cavity side with gingival epithelium. The free gingival margin is where these two epithelia meet in the oral cavity at the lip of the gingival sulcus. The gingival sulcus normally lies between tooth enamel above the cementum and oral sulcular epithelium and it extends from the free gingival margin to its base, the junctional epithelial attachment that covers gingival collagen fibers. The free gingiva is held tightly against the tooth by enclosed, free collagen fibers that extend from just below the enamel-cementum junction.
Periodontitis develops in association with persistent gingivitis caused by the plaque microbiota adhering to enamel. The bacteria extend apically along the enamel to the junctional epithelial attachment at its base. The junctional epithelium has an internal (inner) basal layer of dentally attached (DAT) cells that extend to the cemental-enamel junction. There it becomes continuous with an external (outer) epithelial basal layer that extends coronally in contact with the gingival stroma. Coronally it merges with the apical basal layer of oral sulcular epithelial cells. The dentally attached inner and stromally attached outer layers of the junctional epithelium enclose undifferentiated basal cells that, together with the two basal layers, comprise the dental-epithelial attachment.
The junctional epithelial keratinocytes have lax intercellular anchoring junctions and wide intercellular spaces 1. Interstitial fluid therefore transudes from the underlying stroma through the entire epithelium to provide the DAT keratinocytes with nutrients necessary to support their proliferation and maintain their dental attachment2. The interstitial fluid transudes to the base of the sulcus where the most coronally situated DAT cells are susceptible to disruption of its nutrient content by lysine decarboxylase, a bacterial enzyme3. Lysine decarboxylase irreversibly converts lysine to cadaverine and carbon dioxide, depleting the lysine from the interstitial fluid in this region. The DAT cell proliferation at the junctional epithelial coronal extremity is inhibited. The affected DAT cells release mediators that convert the interstitial fluid into an inflammatory exudate containing neutrophilic granulocytes (neutrophils), the gingival crevicular fluid (GCF). Even healthy gingival sulci contain traces of GCF exudate. Exudation remains minimal because the flow stops whenever the coronal DAT cells are replenished with lysine.
Experimental human gingivitis is a well-established method of investigating the development of gingivitis4. During the first 6 hours after tooth cleaning, viridans streptococci along with actinomyces and other bacteria including Eikenella corrodens colonize the teeth of subjects who are free of gingivitis and periodontitis5. The commensal bacteria comprise a mostly gram positive microbiota that adheres to the gingival margin region of teeth in the oral cavity. The bacteria increase significantly and extend into the gingival sulcus over 4 additional days of no oral hygiene6. During this time, the GCF increasingly exudes from the gingival sulcus in association with microscopic evidence of inflammation7.
The GCF contains serum proteins that are absent from interstitial fluid, and, because of its faster flow and inflammatory nature, it provides plasma proteins, glucose, amino acids and vitamins. Proteins are absent from the interstitial fluid, and their presence promotes the development of a gram negative microbiota within the initial plaque of commensal microbiota8. This gram negative microbiota, is termed the successor microbiota9, and it is a major source of bacterial products that promote inflammation. Within the successor microbiota, Porphyromonas gingivalis, Tanerella fosythensis and Treponema denticola develop as a climax microbiota9, but no one group or individual bacterium is exclusive to gingivitis or periodontitis; various bacteria may be involved.
Gram negative bacteria are a major source of lipopolysaccharide and many of the successor and climax microbiota perform asaccharolytic fermentations. During growth by asaccharolytic fermentation, energy is obtained by the bacteria hydrolyzing proteins to amino acids and metabolizing them anaerobically to ammonia and short chain fatty acids. The lipopolysaccharide and short chain fatty acids induce inflammation and the ammonia creates an alkaline environment, causing calcium phosphate in the GCF exudate to precipitate (calculus). The inflammation becomes evident as gingivitis which then induces the changes that cause periodontitis, especially if the bacteria remain sheltered from cleaning by calculus.
The GCF is an inflammatory exudate that provides the substrates for plaque mass to increase and for the successor microbiota to develop. If there was no GCF exudation, there would be no substrates for the successor microbiota to develop. Oral hygiene is essential to prevent the successor microbiota from developing on the GCF, but not the lysine decarboxylase induction of traces of GCF. Antibodies that inhibit all lysine decarboxylase activity in the oral cavity should therefore retard GCF exudation required for development of the successor and climax microbiota and therefore of gingivitis and chronic periodontitis.
The nutrients in GCF enable the colonies of commensal, gram positive bacteria to thicken at the gingival margin and lip of the sulcus, providing a more anaerobic environment for the successor microbiota to grow. But the GCF also replenishes lysine, causing the DAT cells to stop signaling until lysine again becomes depleted. These cycles of lysine depletion and GCF induction eventually permit enough of the successor microbiota to grow within the commensal bacteria at the gingival margin and extend into the sulcus. There, lipopolysaccharide and metabolic products of the successor microbiota induce gingivitis, which develops into periodontitis if it persists10.
Untreated chronic periodontitis predominates in older humans, in whom it associates with a higher level of pro-inflammatory agents, including an increased risk of cardiovascular and cerebrovascular events and poor control of type II diabetes. Successful periodontal therapy reduces the level of pro-inflammatory agents and the associated risk of these diseases. In aging dogs and cats, bacterial products released from sites of periodontitis into the blood will spread throughout the body and may damage the kidneys, heart, liver and brain.
In humans, twice-daily oral hygiene slows the development of the successor microbiota, but cannot stop the lysine depletion cycles. In addition, professional cleaning every 3-6 months is necessary to remove bacterial plaque, especially if it has calcified. In cats and dogs, a hard diet controls plaque until calculus develops, usually by age 2, when annual scaling and prophylaxis is recommended. In the complete absence of oral hygiene, advanced periodontal disease develops and multiple tooth loss often results by late middle age.
Household pets such as dogs and cats develop severe periodontitis because advances in veterinary medicine have extended their life, and periodontitis has more time to advance. Unfortunately cleaning a household pet's teeth is expensive and undesirable because of a need for anesthesia. On the other hand, many bacterial diseases are efficiently and economically controlled by immunization. Immunization with an appropriate vaccine during a pet's early adolescence, before periodontitis has developed, and repeated immunization to maintain desirable antibody levels, may prevent periodontal disease and its associated illnesses. Immunization as a means of controlling periodontal disease therefore has commercial utility.
Advanced human periodontal disease is a common problem in many developing countries, where it often results in multiple tooth loss by early middle age. For humans, a vaccine as a prophylactic treatment or as an adjunct to therapy for gingivitis and periodontitis would reduce disease occurrence and recurrence and enhance quality of life. A vaccine given early in adolescence before the onset of periodontitis would also be useful for young adults who have poor access to dental care as well as those who follow poor dental hygiene. Therefore, a vaccine for preventing or modulating periodontal disease has economic and practical benefit.
A vaccine is commercially available that purports to control periodontitis in dogs. It consists of a mixture of cell wall and other components of bacterial species associated with periodontitis in dogs, a “Porphyromonas Denticanis-Gulae-Salivosa Bacterin”, P. gingivalis is absent11. There are three shortcomings of this vaccine: (a) its control of dog periodontitis has not been demonstrated because it was tested in a mouse oral cavity where the vaccine inhibited periodontitis associated with artificial infection with only the component organisms12; (b) different gram negative bacteria may replace the inhibited bacteria in vaccinated dogs, causing periodontitis to persist; and (c) its many unknown components increase the likelihood of deleterious side effects. Evidence that this vaccine is safe and effective in dogs is uncertain.